A Cellular and Molecular Basis for the Selective Desmopressin-Induced ACTH Release in Cushing Disease Patients: Key Role of AVPR1b Receptor and Potential Therapeutic Implications

Abstract

The present results provide a cellular and molecular basis to support the desmopressin stimulation test as a reliable, specific test for the diagnosis and postsurgery prognosis of CD. Furthermore, our data indicate that AVPR1b is responsible for the direct/exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

Differentiating between Cushing's disease and pseudo-Cushing's syndrome: comparison of four tests

“…Stimulation with either CRH or desmopressin, a synthetic vasopressin analog, results in a direct release of ACTH (40,41,42). Tirabassi et al (43) reported excellent diagnostic performance as well as perfect diagnostic agreement for the human CRH test and the desmopressin test in a study with a small number of patients with PCS (nZ12), which should be confirmed by future studies.…”

Multiple aberrant hormone receptors in Cushing's syndrome

“…The use of an AVPR1b antagonist completely blocked DDAVP stimulatory effects. Remarkably, only AVPR1b expression was positively correlated with elevated plasma ACTH levels in corticotropinomas (124). Patients with CD respond aberrantly to ghrelin and hexarelin with increased ACTH secretion (125); the expression of ghrelin receptors, GHSR1a and GHS-R1b, in tumor tissue samples from two patients with CD were demonstrated.…”

The New Molecular Landscape of Cushing's Disease

“…It has been reported that such tumors show increased expression of both arginine vasopressin (AVP) [24][25][26][27] and CRH receptors [25,27,28], whereas the opposite is true for the ACTH receptor gene [29].…”

“…The two proteins responsible for transcriptional POMC repression are brahma-related gene 1 (Brg1) and histone deacetylase 2 (HDAC2), which are essential for the regulation of transcriptional activation via modulation of chromatin structure [27,39]. As Brg1 is necessary for stable complex formation between GR and nerve growth factor 1B (NGFI-B) on the one hand, and recruitment of HDAC2 to this complex on the other, its absence impairs the ability of GR to repress POMC transcription, resulting in an increased POMC expression [26,27,36,39]. However, the molecular basis for this reduced expression of Brg1 and HDAC2 has remained elusive.…”

“…Detailed analyses have revealed that all arginine vasopressin receptor (AVPR) subtypes (i.e., 1a, 1b, and 2) are overexpressed in corticotroph adenomas, but AVPR1b seems to play a dominant role in the long-lasting stimulation of ACTH by desmopressin [26]. Accordingly, high expression of AVPR1b in corticotropinomas may play a key role in their hypersecretion of ACTH.…”